PROJECT SUMMARY Smoking rates in people living with HIV (PLWH) exceed 40%, nearly 3x uninfected individuals. Cardiovascular disease (CVD), including myocardial infarction (MI), is common in PLWH, in part due to smoking. Despite availability of smoking cessation pharmacotherapy, cessation rates among PLWH remain low. Frameworks for understanding smoking cessation emphasize biological, psychological, and social factors. However, critical gaps in identifying and addressing biological factors related to tobacco use among PLWH remain. In the general population, the rate at which nicotine is metabolized is an important biomarker of smoking behavior and treatment response. Greater CYP2A6 enzyme activity, as measured by higher nicotine metabolite ratios (NMR), results in: faster nicotine clearance, more cigarettes smoked per day, higher nicotine dependence, greater severity of withdrawal symptoms and reduced cessation. Recent work from our lab found significantly higher NMRs in HIV suggesting effects in HIV may differ. Differences in NMR may be affected by HIV infection and/or antiretroviral therapy (ART). HIV itself may increase NMR as CYP2A6 is induced by inflammation, which may mirror dysregulation caused by HIV infection. ART drugs may alter NMR via other mechanisms: they may reduce NMR by reducing inflammation via viral suppression, reduce NMR via CYP2A6 inhibition, or increase NMR via CYP2A6 induction. And these mechanisms may differ by ART drug. Moreover, the impact of higher NMR on smoking and complications of smoking (e.g., MI) among PLWH are currently unknown. Higher NMR influences smoking topography (e.g., higher puff volume), which is associated with greater exposure to inducers of inflammation and coagulation. While higher NMR increases lung cancer risk, its effect on MI is unknown. We propose to: 1) determine whether NMR is faster after HIV infection, relative to before, 2) determine whether viral suppression decreases NMR and whether the effect differs by ART drugs which do and do not alter CYP2A6 activity, 3) determine whether lower NMR predicts higher smoking cessation rates in PLWH on ART with viral suppression, and 4) determine whether NMR is a risk factor for MI in PLWH. We will conduct retrospective cohort studies with paired specimens for Aims 1 and 2 and nested case-control studies for Aims 3 and 4. Data and specimens will be obtained from the Multicenter AIDS Cohort Study (MACS) /Women's Intra-agency Health Study (WIHS) and the CFAR Network Integrated Clinical Systems (CNICS) databases and specimen repositories. Elucidating the relationship between HIV, ART, and smoking, may lead to the development of targeted interventions for smokers with HIV infection such as adding drugs that decrease CYP2A6 activity or switching off ART drugs that induce CYP2A6. If NMR is a predictor of MI, it will help us identify a subpopulation of PLWH in more urgent need of interventions. Smokers with HIV lose more life years to tobacco use than to HIV, partly due to increases in smoking-related comorbidities including CVD. Thus, interventions targeting HIV+ smokers may substantially reduce mortality globally.